Prognostic Biomarker For Lung Cancer Research Articles

Down-regulation of cytoplasmic PLZF correlates with high tumor grade and tumor aggression in non–small cell lung carcinoma

There are currently no effective prognostic biomarkers for lung cancer. Promyelocytic leukemia zinc finger (PLZF), a transcriptional repressor, has a role in cell cycle progression and tumorigenicity in various cancers. The expression and value of PLZF in lung carcinoma, particularly in the subclass of non-small cell lung carcinoma (NSCLC), has not been studied. Our aim was to study the immunohistochemical expression of PLZF in lung adenocarcinoma and squamous cell carcinoma and correlate the alteration of PLZF expression with tumor differentiation, lymph node metastasis, tumor stage, and overall survival. A total of 296 NSCLCs being mounted on tissue microarray (181 adenocarcinomas and 91 squamous cell carcinomas) were investigated. Moderate to strong expression of PLZF was found in the cytoplasm of all the nonneoplastic respiratory epithelium and most (89.9%) well-differentiated adenocarcinoma. The proportions of moderately differentiated, poorly differentiated adenocarcinoma, and paired lymph node adenocarcinoma metastases that demonstrated negative or only weak PLZF reactivity were 75.6%, 97.2%, and 89.9%, respectively. The expression of PLZF in squamous cell carcinoma was mostly weak or absent and significantly lower than that in adenocarcinoma of the same grade (P < .0005). The loss of cytoplasmic PLZF strongly correlated with high tumor grade and lymph node metastasis in both squamous carcinoma and adenocarcinoma (P < .0001). Down-regulation of PLZF also correlated with higher tumor stage and shorter overall survival (P < .05). These results support a prognostic value for loss of cytoplasmic PLZF expression in the stratification of NSCLC and a possible role of cytoplasmic shift and down-regulation of PLZF in the pathogenesis of NSCLC.

TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is a potential prognostic biomarker in lung cancer.

Epigenetic silencing of tumour suppressors contributes to the development and progression of lung cancer. We recently found that TMEM196 was hypermethylated in lung cancer. This study aimed to clarify its epigenetic regulation, possible roles and clinical significance. TMEM196 methylation correlated with loss of protein expression in chemical-induced rat lung pathologic lesions and human lung cancer tissues and cell lines. 5-aza-2'-deoxycytidine restored TMEM196 expression. Moreover, TMEM196 hypermethylation was detected in 61.2% of primary lung tumours and found to be associated with poor differentiation and pathological stage of lung cancer. Functional studies showed that ectopic re-expression of TMEM196 in lung cancer cells inhibited cell proliferation, clonogenicity, cell motility and tumour formation. However, TMEM196 knockdown increased cell proliferation and inhibited apoptosis and cell-cycle arrest. These effects were associated with upregulation of p21 and Bax, and downregulation of cyclin D1, c-myc, CD44 and β-catenin. Kaplan-Meier survival curves showed that TMEM196 downregulation was significantly associated with shortened survival in lung cancer patients. Multivariate analysis showed that patients with TMEM196 expression had a better overall survival. Our results revealed for the first time that TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is an independent prognostic factor of lung cancer.

Long non-coding RNA functions in lung cancer.

Numerous long non-coding RNAs (lncRNAs) have been discovered as a result of advances in sequencing methods in genomic research. Recent evidence indicates that lncRNAs may serve as gene regulators via various mechanisms, such as translational control. Dysregulation of lncRNAs contributes to the development and progression of several human diseases, notably lung cancer, which is one of the leading causes of cancer-associated death. Recent studies have identified key roles for molecules such as p53 and polycomb repressive complex 2 (PRC2) in carcinogenesis and the anti-carcinogenic action of lncRNAs. These findings point to the potential of lncRNAs as prospective diagnostic and prognostic biomarkers in lung cancer. In this review, we consider the functions of lncRNAs in translational control and discuss their involvement in lung cancer via p53, PRC2, and other pathways. We also consider the effects of modulating the levels and functions of lncRNAs. Further characterization of these lung cancer-associated lncRNAs will provide a better understanding of their potential roles as therapeutic targets.

ING5 inhibits cancer aggressiveness via preventing EMT and is a potential prognostic biomarker for lung cancer.

The proteins of the Inhibitor of Growth (ING) candidate tumor suppressor family are involved in multiple cellular functions such as cell cycle regulation, apoptosis, and chromatin remodeling. ING5 is the new member of the family whose actual role in tumor suppression is not known. Here we show that ING5 overexpression in lung cancer A549 cells inhibited cell proliferation and invasiveness, while ING5 knockdown in lung cancer H1299 cells promoted cell aggressiveness. ING5 overexpression also abrogated tumor growth and invasive abilities of lung cancer cells in mouse xenograft models. Further study showed that ING5 overexpression inhibited EMT indicated by increase of E-cadherin and decrease of N-cadherin, Snail and slug at mRNA and protein levels, which was accompanied with morphological changes. cDNA microarray and subsequent qRT-PCR validation revealed that ING5 significantly downregulated expression of EMT (epithelial to mesenchymal transition)-inducing genes including CEACAM6, BMP2 and CDH11. Clinical study by tissue microarray showed that nuclear ING5 negatively correlated with clinical stages and lymph node metastasis of lung cancer. Furthermore, high level of nuclear ING5 was associated with a better prognosis. Taken together, these findings uncover an important role for ING5 as a potent tumor suppressor in lung cancer growth and metastasis.

NPTX1 is a novel epigenetic regulation gene and associated with prognosis in lung cancer

BackgroundCpG island hypermethylation of gene promoters is a well-known mechanism of epigenetic regulation of tumor related-genes and is directly linked to lung carcinogenesis. Alterations in the pattern of methylation of the NPTX1 gene have not yet been studied in detail in human lung cancer. MethodsMethylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to analyze promoter methylation status, and real-time quantitative reverse transcription-PCR (qRT-PCR) examined mRNA levels. Subsequently, we compared the methylation profile of NPTX1 in samples of neoplastic and non-neoplastic lung tissue taken from the same patients by using quantitative methylation specific PCR (QMSP). ResultsCpG island hypermethylation in promoter of NPTX1 was confirmed in lung cancer cell lines. A significant increase in NPTX1 methylation was identified in lung cancer specimens compared to adjacent noncancerous tissues and that it was negatively correlated with its mRNA expression. The overall survival time among patients carrying methylated NPTX1 tumors was significantly shorter as compared to those with unmethylated NPTX1 tumors (P = 0.011). Moreover, methylation of NPTX1 gene was found to be an independent prognostic factor for poor overall survival based on multivariate analysis models (p = 0.021), as was age ≥60 years old (p = 0.012) and TNM stage (p < 0.001). ConclusionsThese results suggest that NPTX1 hypermethylation and consequent mRNA changes might be an important molecular mechanism in lung cancer. Epigenetic alterations in NPTX1 may serve as potential diagnostic and prognostic biomarkers in lung cancer.

Apolipoprotein C1 (APOC1) as a novel diagnostic and prognostic biomarker for lung cancer: A marker phase I trial.

Tumor cells continuously evolve over time in response to host pressures. However, explanations as to how tumor cells are influenced by the inflammatory tumor microenvironment over time are, to date, poorly defined. We hypothesized that prognostic biomarkers could be obtained by exploring the expression of inflammation-associated genes between early and late stage lung cancer tumor samples. Candidate inflammation-associated genes, apolipoprotein C-1 (APOC1), MMP1, KMO)1, CXCL5, CXCL)7, IL-1α, IL-1β, TNF-α and IL-6 were verified by real-time quantitative polymerase chain reaction. Gene expression profiles and immunofluorescence staining of 30 lung cancer tissues were compared. Expressions of APOC1 and IL-6 mRNA on tumor tissues in late stage disease were significantly higher than in early stage lung cancer samples. Immunofluorescence staining of tumor samples showed that the expression of APOC1 gradually increased from early to late stage in lung cancer patients. The expression levels of IL-6 and APOC1 in tumor samples were positively correlated; however, no prognostic value of APOC1 can be identified in serum samples. We found that the level of tumor APOC1 was highly expressed in late stage lung cancer. Further research is warranted to determine the molecular mechanisms underlying the cross talk of APOC1 and IL-6 in tumor progression. An expanded sample size marker phase II study may lead to the discovery of new lung cancer therapeutics targeting APOC1.

Necrosis and apoptotic index as prognostic factors in non-small cell lung carcinoma: a review

Necrosis and apoptosis represent two pathogenetically distinct types of cell death. Necrosis is associated with pathologic conditions while apoptosis is a physiological process of programmed cell death, which is associated with normal tissue growth and is frequently impaired in various forms of cancer. Tumor necrosis and apoptotic index (AI) have been previously evaluated as prognostic biomarkers in lung cancer, but their exact clinical value remains unclear. The aim of this study was to perform a systematic review of the MEDLINE literature on the prognostic significance of these histopathological markers in patients with non-small cell lung carcinoma (NSCLC). Although a substantial body of evidence suggests that tumor necrosis may be a strong predictor of aggressive tumor behavior and reduced survival in patients with NSCLC, the independent prognostic value of this biomarker remains to be firmly established. Furthermore, previous data on the prognostic significance of apoptotic index in NSCLC are relatively limited and largely controversial. More prospective studies are necessary in order to further validate tumor necrosis and AI as prognostic markers in NSCLC.

Insulin-Like Growth Factor Binding Protein-2 Level Is Increased in Blood of Lung Cancer Patients and Associated with Poor Survival

BackgroundWe recently showed that IGFBP2 is overexpressed in primary lung cancer tissues. This study aims to determine whether IGFBP2 is elevated in blood samples of lung cancer patients and whether its level is associated with clinical outcomes.Methodology/Principal FindingsPlasma IGFBP2 levels were determined blindly by enzyme-linked immunosorbent assay in 80 lung cancer patients and 80 case-matched healthy controls for comparison. We analyzed blood samples for IGFBP2 levels from an additional 84 patients with lung cancer and then tested for associations between blood IGFBP2 levels and clinical parameters in all 164 lung cancer patients. All statistical tests were two-sided and differences with p<0.05 were considered significant. The mean plasma concentration of IGFBP2 in lung cancer patients was significantly higher than that in healthy controls (388.12±261.00 ng/ml vs 219.30±172.84 ng/ml, p<0.001). IGFBP2 was increased in all types of lung cancer, including adenocarcinoma, squamous cell cancer, and small-cell cancer, regardless of patients’ age, sex, or smoking status. IGFBP2 levels were mildly but significantly associated with tumor size and were significantly higher in stage IV than stage I or III disease. A multivariate analysis showed that lung cancer patients whose blood IGFBP2 was higher than 160.9 ng/ml had a poor survival outcome, with a hazard ratio of 8.76 (95% CI 1.12-68.34, p=0.038 after adjustment for tumor size, pathology, and stage). The median survival time for patients with blood IGFBP2 >160.9 ng/ml is 15.1 months; whereas median survival time was 128.2 months for the patients whose blood IGFBP2 was ≤160.9 ng/ml (p =0.0002).Conclusions/SignificanceBlood IGFBP2 is significantly increased in lung cancer patients. A high circulating level of IGFBP2 is significantly associated with poor survival, suggesting that blood IGFBP2 levels could be a prognostic biomarker for lung cancer.

Investigation of Complement Activation Product C4d as a Diagnostic and Prognostic Biomarker for Lung Cancer

There is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments. We assessed complement activation in four bronchial epithelial and seven lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; bronchoalveolar lavage supernatants from patients with lung cancer (n = 50) and nonmalignant respiratory diseases (n = 22); and plasma samples from advanced (n = 50) and early lung cancer patients (n = 84) subjects with inflammatory lung diseases (n = 133), and asymptomatic individuals enrolled in a lung cancer computed tomography screening program (n = 190). Two-sided P values were calculated by Mann-Whitney U test. Lung cancer cells activated the classical complement pathway mediated by C1q binding that was inhibited by phosphomonoesters. Survival was decreased in patients with high C4d deposition in tumors (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 1.18 to 7.91). C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients compared with patients with nonmalignant respiratory diseases (0.61 ± 0.87 vs 0.16 ± 0.11 µg/mL; P < .001). C4d levels in plasma samples from lung cancer patients at both advanced and early stages were also increased compared with control subjects (4.13 ± 2.02 vs 1.86 ± 0.95 µg/mL, P < 0.001; 3.18 ± 3.20 vs 1.13 ± 0.69 µg/mL, P < .001, respectively). C4d plasma levels were associated with shorter survival in patients at advanced (HR = 1.59; 95% CI = 0.97 to 2.60) and early stages (HR = 5.57; 95% CI = 1.60 to 19.39). Plasma C4d levels were reduced after surgical removal of lung tumors (P < .001) and were associated with increased lung cancer risk in asymptomatic individuals with (n = 32) or without lung cancer (n = 158) (odds ratio = 4.38; 95% CI = 1.61 to 11.93). Complement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer.

Abstract 2357: Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer.

Abstract Background: Placental growth factor (PIGF) is a proangiogenic factor, belonging to the VEGF family. It binds to VEGF receptor 1(VEGFR-1) and stimulates the growth, migration and survival of endothelial cells. PIGF also activates and attracts macrophages that release angiogenic molecules. Increased expression of PIGF has correlated with poor survival of patients in several solid tumors. However, PIGF expression is not consistently elevated in all malignancies. No reports on the clinical implications of PIGF expression in metastatic or recurrent non-small cell lung cancer (NSCLC) are currently available. We investigate the clinical significance of PIGF expression in metastatic or recurrent NSCLC. Patients and methods: A retrospective review was done for seventy four patients with metastatic or recurrent NSCLC. Immunohistochemical staining for PIGF and its receptor VEGF-R1, neurophilin-1 was performed. Results: Of 74 patients with NSCLC, 73 patients were positive for PIGF, and 72 patients were positive for neurophilin-1. For PIGF expression, significant correlations were demonstrated with female (p=0.007) and nonsquamous histology (p=0.045). Thirty five patients (47%) were classified into low PIGF expression groups, whereas 38 patients (51%) were grouped as showing high PIGF expression. Survival time for patients with high PIGF expressing NSCLC was significantly longer than that for patients displaying low PIGF expression (median survival time, 15.1 months vs. 9.0 months[log-rank, p=0.01]). However, the difference in time to progression between two groups was not statistically significant (median time to progression, 5.1 months vs. 3.9 months [log-rank, p=0.24]). Conclusions: Low expression of PIGF is associated with poor prognosis in patients with metastatic or recurrent NSCLC. Further studies on larger patients populations are warranted to validate the utility of PIGF as a prognostic biomarker in lung cancer. Citation Format: Jung Hoon Kim, Tae Jung Kim, Kyu Sang Lee, Yun Hwa Jung, In Sook Woo, Sook Hee Hong, Chi Wha Han, Jae Kil Park, Jae Ho Byun. Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2357. doi:10.1158/1538-7445.AM2013-2357

Abstract 2361: SNP (-617G&amp;gt;A) in ARE-like loci of the NRF2 gene: a new biomarker for prognosis of lung adenocarcinoma.

Abstract Purpose: Accumulating evidence suggests nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays an important role as cellular defense, tumor suppression, and oncogenesis. However, little information is available as to the genetic polymorohisms of the NRF2 gene and their clinical relevance. We aimed to validate the NRF2 gene as a prognostic biomarker in lung cancer. Experimental Design: We prepared genomic DNA from 392 Japanese patients with primary lung cancer and detected a SNP (c.-617C&amp;gt;A) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We analyzed an association between the NRF2 gene and overall survival. Results: We detected homozygous (A/A) and heterozygous (C/A) alleles with the SNP (c.-617C&amp;gt;A) in 24 (6.2%) and 147 (38.0%) patients, respectively. The frequency of the homozygote (A/A) was four-fold higher in females than in males (11.0% versus 2.7%). Multivariate logistic regression models including standard lung cancer factors revealed that the homozygous alleles (c.-617A/A) were significantly related to gender. Interestingly, lung cancer patients carrying the homozygous alleles (c.-617A/A) exhibited remarkable survival over 1,700 days after surgical operation (log-rank p=0.021). Conclusion: The homozygous allele (c.-617A/A) in the NRF2 gene is considered to be a prognostic biomarker for assessing both the gender-related risk of lung adenocarcinoma in the non-smoking sub-population and their overall survival. Citation Format: Yasuko Okano, Yasushi Ichikawa, Yohei Miyagi, Yutaka Natsumeda, Toshihisa Ishikawa. SNP (-617G&amp;gt;A) in ARE-like loci of the NRF2 gene: a new biomarker for prognosis of lung adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2361. doi:10.1158/1538-7445.AM2013-2361

Rapid detection of exon 2-deleted AIMP2 mutation as a potential biomarker for lung cancer by molecular beacons

Exon 2 deletion in aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) has been suggested to be associated with the progression of various cancers such as lung and ovarian cancers. However, few studies have been conducted regarding detection and relevance of exon 2-deleted AIMP2 (AIMP2-DX2) mutation to a specific cancer. Here, we demonstrate the rapid and simple detection of the AIMP2-DX2 mutation by molecular beacons and its relation to lung cancer. Real-time PCR with molecular beacons allowed a sensitive detection of the AIMP2-DX2 mutation as low as 0.3pg initial template. Dual-conjugated liposomes with folate and molecular beacon enabled fluorescence imaging of cancer cells harboring the AIMP2-DX2 mutation with high resolution. Association of the AIMP2-DX2 mutation with lung cancer was shown by analyzing tissue samples from lung cancer patients using real-time PCR. Approximately, 60% of lung cancer patients harbored the AIMP2-DX2 mutation, which implies a potential of the AIMP2-DX2 mutation as a prognostic biomarker for lung cancer. Molecular beacon-based approaches will find applications in the simple and rapid detection of mutations on nucleotides for diagnosing and monitoring the progression of relevant cancer.

A Mathematical Model for MicroRNA in Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Lack of early detection and limited options for targeted therapies are both contributing factors to the dismal statistics observed in lung cancer. Thus, advances in both of these areas are likely to lead to improved outcomes. MicroRNAs (miRs or miRNAs) represent a class of non-coding RNAs that have the capacity for gene regulation and may serve as both diagnostic and prognostic biomarkers in lung cancer. Abnormal expression patterns for several miRNAs have been identified in lung cancers. Specifically, let-7 and miR-9 are deregulated in both lung cancers and other solid malignancies. In this paper, we construct a mathematical model that integrates let-7 and miR-9 expression into a signaling pathway to generate an in silico model for the process of epithelial mesenchymal transition (EMT). Simulations of the model demonstrate that EGFR and Ras mutations in non-small cell lung cancers (NSCLC), which lead to the process of EMT, result in miR-9 upregulation and let-7 suppression, and this process is somewhat robust against random input into miR-9 and more strongly robust against random input into let-7. We elected to validate our model in vitro by testing the effects of EGFR inhibition on downstream MYC, miR-9 and let-7a expression. Interestingly, in an EGFR mutated lung cancer cell line, treatment with an EGFR inhibitor (Gefitinib) resulted in a concentration specific reduction in c-MYC and miR-9 expression while not changing let-7a expression. Our mathematical model explains the signaling link among EGFR, MYC, and miR-9, but not let-7. However, very little is presently known about factors that regulate let-7. It is quite possible that when such regulating factors become known and integrated into our model, they will further support our mathematical model.

Correlation of a Serological Proteome and Lung Cancer Prognosis

Abstract Background To study the correlation of the lost goodwill target (LGT) proteome and the prognosis in patients with lung cancer and explore whether the LGT proteome can be used as an accurate and reliable prognostic biomarker for lung cancer. Methods One hundred eighty eight patients with lung cancer were enrolled in the Shanxi Cancer Hospital, China. For each patient, LGT test in serum was performed using the technique SELDITOF-MS after the pathological diagnosis. Kaplan- Meier survival analysis, Log-rank test and multivariate Cox proportional hazards regression analysis were performed to explore the influence of LGT different expression on the prognosis. Results The median survival times were 865 and 514 days in the LGT negative and LGT positive groups, respectively. There was statistically significant difference between the two survival curves, and the survival rate of the LGT negative group was higher than that of the LGT positive (χ2=5.757, P=0.016). Multivariate Cox proportional hazards regression analysis confirmed that the LGT proteome (RR=1.5, 95% CI 1.075~2.196, P=0.019) predicted for death. Conclusion Our results showed that the prognosis of lung cancer is related to LGT proteome expression, suggesting that LGT may be regarded as one of the serological protein that signs a poor prognosis in lung cancer and has important clinical significance in predicting illness development.

Nkx2-1: a novel tumor biomarker of lung cancer

Nkx2-1 (Nkx homeobox-1 gene), also known as TTF-1 (thyroid transcription factor-1), is a tissue-specific transcription factor of the thyroid, lung, and ventral forebrain. While it has been shown to play a critical role in lung development and lung cancer differentiation and morphogenesis, molecular mechanisms mediating Nkx2-1 cell- and tissue-specific expression in normal and cancerous lungs have yet to be fully elucidated. The recent identification of prognostic biomarkers in lung cancer, particularly in lung adenocarcinoma (ADC), and the different reactivity of patients to chemotherapeutic drugs have opened new avenues for evaluating patient survival and the development of novel effective therapeutic strategies. The function of Nkx2-1 as a proto-oncogene was recently characterized and the gene is implicated as a contributory factor in lung cancer development. In this review, we summarize the role of this transcription factor in the development, diagnosis, and prognosis of lung cancer in the hope of providing insights into the utility of Nkx2-1 as a novel biomarker of lung cancer.

High expression of miR-21 and miR-155 predicts recurrence and unfavourable survival in non-small cell lung cancer

We synthesised the evidence of microRNAs as prognostic biomarkers in lung cancer. Studies were identified by searching PubMed, Embase and Web of Science until March 2012. Descriptive characteristics for studies were described and an additional meta-analysis for two specific microRNAs (miR-21 and miR-155) which were studied extensively was performed. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated. The median study size was 88 patients (interquartile range [IQR]=53–193) and the median HR in the studies that reported statistically significant results was 2.855 (IQR=2.01–5.035). For the studies evaluating miR-21’s association with clinical outcomes, the pooled HR suggested that high expression of miR-21 has a negative impact on overall survival (OS) in non-small cell lung cancer (NSCLC) (HR=2.32[1.17–4.62], P<0.05) and recurrence-free survival (RFS)/cancer-specific survival (CSS) in lung adenocarcinoma (HR=2.43[1.67–3.54], P<0.001). As for miR-155, the pooled HR for OS was 2.09 (95%CI: 0.68–6.41, P>0.05) which was not statistically significant, but for RFS/CSS was 1.42 (95% CI: 1.10–1.83, P=0.007). These results indicate that microRNAs show promising associations with prognosis in lung cancer; moreover, specific microRNAs such as miR-21 and miR-155 can predict recurrence and poor survival in NSCLC.

Research Resource: Diagnostic and Therapeutic Potential of Nuclear Receptor Expression in Lung Cancer

Lung cancer is the leading cause of cancer-related death. Despite a number of studies that have provided prognostic biomarkers for lung cancer, a paucity of reliable markers and therapeutic targets exist to diagnose and treat this aggressive disease. In this study we investigated the potential of nuclear receptors (NRs), many of which are well-established drug targets, as therapeutic markers in lung cancer. Using quantitative real-time PCR, we analyzed the expression of the 48 members of the NR superfamily in a human panel of 55 normal and lung cancer cell lines. Unsupervised cluster analysis of the NR expression profile segregated normal from tumor cell lines and grouped lung cancers according to type (i.e. small vs. non-small cell lung cancers). Moreover, we found that the NR signature was 79% accurate in diagnosing lung cancer incidence in smokers (n = 129). Finally, the evaluation of a subset of NRs (androgen receptor, estrogen receptor, vitamin D receptor, and peroxisome proliferator-activated receptor-γ) demonstrated the therapeutic potential of using NR expression to predict ligand-dependent growth responses in individual lung cancer cells. Preclinical evaluation of one of these receptors (peroxisome proliferator activated receptor-γ) in mouse xenografts confirmed that ligand-dependent inhibitory growth responses in lung cancer can be predicted based on a tumor's receptor expression status. Taken together, this study establishes NRs as theragnostic markers for predicting lung cancer incidence and further strengthens their potential as therapeutic targets for individualized treatment.

MicroRNAs – Important Molecules in Lung Cancer Research

MicroRNAs (miRNA) are important regulators of gene expression. They are involved in many physiological processes ensuring the cellular homeostasis of human cells. Alterations of the miRNA expression have increasingly been associated with pathophysiologic changes of cancer cells making miRNAs currently to one of the most analyzed molecules in cancer research. Here, we provide an overview of miRNAs in lung cancer. Specifically, we address biological functions of miRNAs in lung cancer cells, miRNA signatures generated from tumor tissue and from patients’ body fluids, the potential of miRNAs as diagnostic and prognostic biomarker for lung cancer, and its role as therapeutic target.

Interferon (Alpha, Beta and Omega) Receptor 2 Is a Prognostic Biomarker for Lung Cancer

Objectives: It has been reported that the type I interferon receptor subunit, interferon (alpha, beta and omega) receptor 2 (IFNAR2), is overexpressed in several malignancies, primarily adenocarcinomas (ADCs); however, the biological significance of IFNAR2 in human lung cancer has not yet been studied. Methods: Immunohistochemical analysis of 113 surgically resected lung specimens was performed, and the results were evaluated in association with clinical variables, including survival. Serum concentrations of IFNAR2 were also determined by an enzyme-linked immunosorbent assay in 157 lung cancer patients and 164 healthy volunteers. Results: IFNAR2 overexpression was observed in all histological types of lung cancer examined. Furthermore, strong IFNAR2 expression was associated with shorter progression-free survival (PFS) and overall survival (OS) (p < 0.0001 and p = 0.0110, respectively) in non-small cell lung cancer patients. Multivariate analyses confirmed its independent prognostic value for PFS and OS (p < 0.0001 and p = 0.0222, respectively). IFNAR2 serum levels were also significantly higher in lung cancer patients than in healthy volunteers (p < 0.0001). Conclusions: IFNAR2 overexpression was observed in various histological types of lung cancer, and appears to be associated with lung cancers that behave aggressively. The results of this study strongly support the potential of IFNAR2 to be a prognostic biomarker for lung cancer.

Integrated analyses of copy number variations and gene expression in lung adenocarcinoma.

Numerous efforts have been made to elucidate the etiology and improve the treatment of lung cancer, but the overall five-year survival rate is still only 15%. Identification of prognostic biomarkers for lung cancer using gene expression microarrays poses a major challenge in that very few overlapping genes have been reported among different studies. To address this issue, we have performed concurrent genome-wide analyses of copy number variation and gene expression to identify genes reproducibly associated with tumorigenesis and survival in non-smoking female lung adenocarcinoma. The genomic landscape of frequent copy number variable regions (CNVRs) in at least 30% of samples was revealed, and their aberration patterns were highly similar to several studies reported previously. Further statistical analysis for genes located in the CNVRs identified 475 genes differentially expressed between tumor and normal tissues (p<10−5). We demonstrated the reproducibility of these genes in another lung cancer study (p = 0.0034, Fisher's exact test), and showed the concordance between copy number variations and gene expression changes by elevated Pearson correlation coefficients. Pathway analysis revealed two major dysregulated functions in lung tumorigenesis: survival regulation via AKT signaling and cytoskeleton reorganization. Further validation of these enriched pathways using three independent cohorts demonstrated effective prediction of survival. In conclusion, by integrating gene expression profiles and copy number variations, we identified genes/pathways that may serve as prognostic biomarkers for lung tumorigenesis.